The present invention relates to a process for the preparation of cis 5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid and, more particularly, it relates to a process for the isomerization of trans-5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid into the corresponding cis isomer, an intermediate useful for the synthesis of sulindac.
Sulindac, cis 5-fluoro-2-methyl-1-[p-(methylsulphinyl)benzyliden]inden-3-acetic acid, a known anti-inflammatory drug (The Merck Index XII ed., page 1536, no. 9155) is generally prepared according to the synthetic scheme herein below reported, as described in the U.S. Pat. No. 3,654,349 (Merck). 
wherein R is hydrogen or a C1-C6 alkyl.
The condensation between 5-fluoro-2-methyl-inden-3-acetic acid (or an ester thereof) and p-methylthiobenzaldehyde is carried out in methanol, in the presence of sodium methoxide.
The drawback of the condensation described in U.S. Pat. No. 3,654,349 is that the intermediate III-cis is obtained in admixture with remarkable amounts ( greater than 10%) of the III-trans isomer, so making necessary an isomerization reaction as described, for example, in the U.S. Pat. No. 3,692,651 (Merck).
The isomerization is carried out on a mixture of sulindac (cis isomer) and of its trans isomer or on trans-sulindac by treating with iodine or by irradiating with ultra violet light.
A method for carrying out the condensation reaction without the formation of the III-trans isomer is described in the European patent application no. 0 206 241 (Zambon). We have now found a method for the isomerization of trans 5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid.
Therefore, object of the present invention is an isomerization process of trans 5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid consisting in treating the sodium salt of trans 5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid in methanol and in the presence of a base at the temperature of 70xc2x12xc2x0 C.
Examples of bases, which can be used in the present process, are alkali or alkaline-earth hydroxides or C1-C4 alkoxides, preferably sodium hydroxide or C1-C4 alkoxides.
Still more preferably sodium methoxide is used.
Under the conditions of the process object of the present invention, the isomerization of trans 5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid to cis 5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid and the contemporaneous precipitation of the cis isomer are observed.
In such a way, the cis isomer comes out of the reaction equilibrium and the isomerization goes on up to a practically complete conversion.
The process object of the present invention can be used for the isomerization of trans 5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid or of cis-trans mixtures of 5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid prepared by one of the synthetic methods described in the literature.
The working conditions of the present process allow also the isomerization of the exo somer of the compound of formula III, when it is present in the mixture to be isomerized.
In a preferred embodiment, the process object of the present invention is used to obtain cis 5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid directly from the reaction mixture of 5-fluoro-2-methyl-inden-3-acetic acid with p-methylthiobenzaldehyde in methanol and sodium methoxide.
In this way, at the end of the condensation reaction, the reaction mixture is heated at 70xc2x12xc2x0 C. for some hours and then cooled at a room temperature, directly obtaining cis 5-fluoro-2-methyl-1-[p-(methylthio)benzyliden]inden-3-acetic acid with a content of trans isomer lower than 0.5%, suitable for the preparation of sulindac.